What alternative treatments should be considered for a patient with major depressive disorder or generalized anxiety disorder who has not responded to Lexapro (escitalopram) after at least 4-6 weeks of treatment at a therapeutic dose?

What to Try After Lexapro Fails

Switch to a different second-generation antidepressant—specifically bupropion, venlafaxine, or sertraline—as these show equivalent 25% remission rates in treatment-resistant depression and are the evidence-based first-line strategy. 1, 2

Why Switching is Preferred Over Other Strategies

• All second-generation antidepressants demonstrate equivalent ultimate efficacy for major depressive disorder, with no clinically significant differences in response rates, remission rates, or quality of life improvements. 1, 2

• The landmark STAR*D trial demonstrated that approximately 1 in 4 patients (25%) became symptom-free after switching medications, with no difference among bupropion, sertraline, and venlafaxine. 1, 2

• Switching to a different class is the evidence-based approach rather than combining agents. 2

Selecting the Right Medication Based on Your Symptoms

Choose Bupropion If:

• You experienced sexual dysfunction or weight gain on Lexapro, as bupropion has lower discontinuation rates than other augmentation strategies. 2
• You have prominent fatigue or psychomotor retardation (feeling slowed down physically and mentally). 2

Choose Venlafaxine If:

• You have depression with prominent anxiety symptoms, as venlafaxine showed better response rates than fluoxetine in patients with comorbid anxiety. 1, 3
• You have melancholic features (severe depression with loss of pleasure in all activities). 1

Choose Sertraline If:

• You need a well-studied option with broad evidence across multiple populations. 1, 2

Consider Duloxetine If:

• You have comorbid chronic pain conditions alongside depression. 2

Consider Mirtazapine If:

• You have depression with prominent insomnia and poor appetite, as mirtazapine has sedating and appetite-stimulating effects. 2
• You need faster symptom relief, as mirtazapine shows significantly faster onset of action (1-2 weeks) compared to SSRIs like Lexapro. 1, 2

Setting Realistic Expectations

• 38% of patients will not respond and 54% will not achieve remission within 6-12 weeks, regardless of which strategy is chosen. 1, 2

• This means you should have contingency plans ready and understand that finding the right medication may require multiple attempts. 2

Critical Monitoring Requirements

• Schedule contact (in-person or telephone) at week 1 to assess early adverse effects and adherence. 2

• Implement weekly monitoring at weeks 2-4 for suicidal ideation, behavioral activation, and treatment response. 2

• At each contact, specifically assess: ongoing depressive symptoms, suicide risk, adverse effects, adherence to treatment, and new environmental stressors. 2

• If no adequate response occurs within 6-8 weeks, modify treatment again. 1

When to Consider Augmentation Instead

• Augmentation with bupropion (150-300mg daily) may be considered as a second-line strategy if switching fails, as low-quality evidence shows it decreases depression severity more than buspirone with lower discontinuation rates. 2

• Cognitive behavioral therapy augmentation is equally effective as pharmacologic augmentation, with no difference in response, remission, or depression severity. 2

Common Pitfalls to Avoid

• Do not combine duloxetine and mirtazapine except in highly selected inpatient settings after exhausting all guideline-recommended alternatives, due to significant risk of serotonin syndrome (tremor, diarrhea, delirium, neuromuscular rigidity, hyperthermia). 2

• Ensure adequate dose and duration (at least 6-8 weeks at therapeutic dose) before declaring Lexapro a failure. 1

• Continue successful treatment for 4-9 months after response for first episode, or longer if you've had 2 or more episodes. 1